Alzheimer's Disease
Alzheimer's disease (also called “AD”, “senile dementia of the Alzheimer Type (SDAT)” or “Alzheimer's”) is a neurodegenerative disorder of the central nervous system (“CNS”). AD is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features.
AD is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Both amyloid plaques (“AP”) and neurofibrillary tangles (“NFT”) are clearly visible by microscopy in brains of those afflicted with AD. Plaques are dense, mostly insoluble deposits of amyloid-beta (“Aβ”) protein and cellular material outside and around neurons. NFT are aggregates of the microtubule-associated protein “tau”, which have become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of ageing, the brains of AD patients have a greater number of such plaques and tangles in specific brain regions, such as the temporal lobe.
AD is characterized histologically by the presence of extracellular amyloid deposits in the brain, together with widespread neuronal loss. Extracellular amyloid deposits are known as neuritic or senile plaques. Amyloid deposits also may be found within and around blood vessels. The main protein constituent of AD and AD-like senile plaques is Aβ. Aβ may be detected in plasma and cerebrospinal fluid (“CSF”) in vivo, and in cell culture media in vitro.
The terms “amyloid peptide” “amyloid β peptide” and “Aβ” are used interchangeably herein to refer to the family of peptides generated through proteolytic processing of the amyloid precursor protein (APP).
APP exists as three different spliced isoforms, one having 770 amino acids (isoform a) (SEQ ID NO:1), one having 751 amino acids (isoform b) (SEQ ID NO:2), and one having 695 amino acids (SEQ ID NO:3). The term “APP” as used herein refers to all three isoforms. The terms “amyloid peptide” “amyloid β peptide” and “Aβ” include, but are not limited to, Aβ40 (SEQ ID NO:4), Aβ42 (SEQ ID NO:5) and Aβ43 (SEQ ID NO:6). The two major forms of Aβ are Aβ40 (SEQ ID NO:4), corresponding to a 40 amino acid-long peptide and Aβ42 (SEQ ID NO:5), corresponding to a 42 amino acid-long peptide. Aβ43 (SEQ ID NO:6) corresponds to a 43 amino acid-long Aβ peptide.
It generally is believed that brain lipids are intricately involved in Aβ-related pathogenic pathways. The Aβ peptide is the major proteinaceous component of the amyloid plaques found in the brains of AD patients and is regarded by many as the culprit of the disorder. The amount of extracellular Aβ accrued is critical for the pathobiology of AD and depends on the antagonizing rates of its production/secretion and its clearance. Studies have shown that neurons depend on the interaction between Presenilin 1 (“PS1”) and Cytoplasmic-Linker Protein 170 (“CLIP-170”) to both generate Aβ and to take it up through the lipoprotein receptor related protein (“LRP”) pathway. Further to this requirement, formation of Aβ depends on the assembly of key proteins in lipid rafts (“LRs”). The term “lipid rafts” as used herein refers to membrane microdomains enriched in cholesterol, glycosphingolipids and glucosylphosphatidyl-inositol-(GPI)-tagged proteins implicated in signal transduction, protein trafficking and proteolysis. Within the LRs it is believed that Aβ's precursor, Amyloid Precursor Protein (“APP”), a type I membrane protein, is cleaved first by the protease β-secretase (BACE) to generate the C-terminal intermediate fragment of APP, CAPPβ, which remains embedded in the membrane. CAPPβ subsequently is cleaved at a site residing within the lipid bilayer by γ-secretase, a high molecular weight multi-protein complex containing presenilin, (PS1/PS2), nicastrin, PEN-2, and APH-1 or fragments thereof. Aβ finally is released outside the cell, where it may: i) start accumulating following oligomerization and exerting toxicity to neurons, or ii) be removed either by mechanisms of endocytosis (involving apolipoprotein-E (apoE) and LRP or Scavenger Receptors) or by degradation by extracellular proteases including insulin-degrading enzyme (IDE) and neprilysin.
It generally is believed that soluble Aβ oligomers, prior to plaque buildup, exert neurotoxic effects leading to neurodegeneration, synaptic loss and dementia. Further, increased Aβ levels may result from abnormal lipid accumulation, thereby producing altered membrane fluidity and lipid raft composition.
The presence of NFT is a characteristic of AD brains. These aggregations of hyperphosphorylated tau protein also are referred to as “Paired Helical filaments” (PHF). The role of PHF, whether as a primary causative factor in AD or in a more peripheral role, is uncertain. However, the accumulation of PHF cause the destabilization of the microtubule network, thus compromising neuronal scaffolding and disrupting cellular trafficking and signal transduction/communication, and leading to neuronal death.
NFT are not specific to AD; NFT also are seen in Creutzfeldt-Jakob disease, Supranuclear Palsy, corticobasal neurodegeneration and Frontaltemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17). This suggests that NFT may represent endpoints leading to neurodegeneration, which may be generated by a number of causative events/insults.
Leptin
Leptin is a helical protein secreted by adipose tissue, which acts on a receptor site in the ventromedial nucleus of the hypothalamus to curb appetite and increase energy expenditure as body fat stores increase. Leptin levels are 40% higher in women, and show a further 50% rise just before menarche, later returning to baseline levels. Leptin levels are lowered by fasting and increased by inflammation.
Human genes encoding both leptin and the leptin receptor site have been identified. Laboratory mice having mutations on the ob gene, which encodes leptin, become morbidly obese, diabetic, and infertile; administration of leptin to these mice improves glucose tolerance, increases physical activity, reduces body weight by 30%, and restores fertility. Mice with mutations of the db gene, which encodes the leptin receptor, also become obese and diabetic but do not improve with administration of leptin. Although mutations in both the leptin and leptin receptor genes have been found in a small number of morbidly obese human subjects with abnormal eating behavior, the majority of obese persons do not show such mutations, and have normal or elevated circulating levels of leptin. The immune deficiency seen in starvation may result from diminished leptin secretion. Mice lacking the gene for leptin or its receptor show impairment of T-cell function, and, in laboratory studies, leptin has induced a proliferative response in human CD4 lymphocytes.
Leptin also controls insulin sensitivity. Within the CNS, leptin crosses the blood brain barrier to bind specific receptors in the brain to mediate food intake, body weight and energy expenditure. In general, (i) leptin circulates at levels proportional to body fat; (ii) leptin enters the CNS in proportion to its plasma concentration; (iii) leptin receptors are found in brain neurons involved in regulating energy intake and expenditure; and (iv) leptin controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalmus.
It generally is believed that leptin inhibits the activity of neurons that contain neuropeptide Y (NPY) and agouti-related peptide (AgRP), and increases the activity of neurons expressing α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of appetite; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the receptor at which α-MSH acts in the brain are linked to obesity in humans.
It is not known how disturbances of production and aggregation of Aβ peptide give rise to the pathology of AD or other progressive cognitive disorders. There remains a need for clinical therapy and diagnostic methods of progressive cognitive disorders related to accumulation of neurofibrillary tangles.